slide source: leptin acts in arcuate nucleus in hypothalamus via the jak/stat pathway obese and...

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LEPTIN acts in arcuate nucleus in hypothalamus

Via the JAK/STAT pathwayObese and T2DM often insulin leptin

resistanceNot a good treatment for weight loss

Up regulated during puberty


resistinElevated in insulin resistance and t2DMInterferes with insulin receptor signaling

Receptor still unknownToo much-BAD


AdiponectinDecreased in obesity, insulin

resistance and T2DM (NIDDM)Associated with Cardiovascular health

Acts on many tissues (liver and muscle)

Associated with Insulin SensitivityVarious forms in circulation-monomer

to multimer G protein coupled, 2 receptors


Links between obesity and T2DM

Most T2DM are obese

Adipocytes make hormones that effect overall body insulin sensitivity

Weight loss can reverse T2DM (early)

One diabetes drug activates an adipocyte transcription factor


Excess Adipose Tissue = ObesityExcess Adipose Tissue = Obesity

Principles of Energy MetabolismPrinciples of Energy Metabolism


Body Energy Stores of Lean 70-kg ManBody Energy Stores of Lean 70-kg Man

Adipose tissue triglyceride = Adipose tissue triglyceride =

120,000120,000 kcal kcal

Muscle triglyceride =

3000 kcal

Liver triglyceride = 450 kcal

Liver glycogen = 400 kcal

Muscle glycogen =

2500 kcal


Obesity Is Caused by Long-Term Positive Obesity Is Caused by Long-Term Positive Energy BalanceEnergy Balance

FatFatStoresStores


Components of Daily Energy ExpenditureComponents of Daily Energy Expenditure

Segal KR et al. Am J Clin Nutr. 1984;40:995-1000.

Thermic effect of feeding

Energy expenditure of physical activity

Resting energy expenditure

Sedentary Person (1800 kcal/d)

Physically Active Person (2200 kcal/d)

8%8% 17%17%

75%75%

8%8%

60%60%

32%32%


Components of Daily Energy ExpenditureComponents of Daily Energy Expenditure Energy expended by physical activity depends on Energy expended by physical activity depends on the the intensity and durationintensity and duration of activities and is the most of activities and is the most variable component of E expenditure. variable component of E expenditure. During high-intensity aerobic exercise (During high-intensity aerobic exercise (vigorous vigorous running or cycling),running or cycling), E consumed by working muscles E consumed by working muscles can increase more than 50-fold, causing a can increase more than 50-fold, causing a 15-fold 15-fold increase in total energy expenditure.increase in total energy expenditure. Obese individuals require the same amount of Obese individuals require the same amount of energy to perform the same amount of work when energy to perform the same amount of work when body weight is supported as do normal weight body weight is supported as do normal weight individuals. individuals. In fact, obese persons expend more energy for the In fact, obese persons expend more energy for the same level of activity when the activity is weight-same level of activity when the activity is weight-bearing because of the increased work involved in bearing because of the increased work involved in carrying more weightcarrying more weight


Relationship between Tissue Energy Relationship between Tissue Energy Expenditure and MassExpenditure and Mass

REE = Resting energy expenditure

Ene

rgy

Exp

endi

ture

(%

RE

E)

Liver, Brain, Kidneys, Gut, Heart

Tissue energy expenditure

Tissue weight

Weight (%

Body W

eight)

80

60

40

20

0SkeletalMuscle

AdiposeTissue,Lean

Person

AdiposeTissue,ObesePerson


Relationship between Tissue Energy Expenditure Relationship between Tissue Energy Expenditure and Mass and Mass

Different body tissues have markedly different Different body tissues have markedly different resting E requirements. Organs that have large resting E requirements. Organs that have large metabolic demands, such as the liver, gut, brain, metabolic demands, such as the liver, gut, brain,

kidney, and heart, have the highest energy kidney, and heart, have the highest energy requirements per gram of tissue. In a lean adult, requirements per gram of tissue. In a lean adult, these organs account for approximately these organs account for approximately 75% of 75% of

resting E expenditureresting E expenditure, although they constitute only , although they constitute only 10% of total body weight. 10% of total body weight. In contrast, resting In contrast, resting skeletal muscle consumes only 20% of resting skeletal muscle consumes only 20% of resting

metabolic rate, although it represents approximately metabolic rate, although it represents approximately 40% of total body weight. Adipose tissue consumes 40% of total body weight. Adipose tissue consumes

less than 5% of resting metabolic rate but usually less than 5% of resting metabolic rate but usually accounts for approximately 20% of body weight.accounts for approximately 20% of body weight.


Regulation of Food IntakeRegulation of Food Intake

BrainBrain

NPYAGRPgalanin

Orexin-Adynorphin

StimulateStimulateα-MSHCRH/UCNGLP-I

CARTNE5-HT

InibitInibit

Central SignalsCentral Signals

Glucose

CCK, GLP-1,Apo-A-IVVagal afferents

Insulin

Ghrelin

Leptin

Cortisol

Peripheral signalsPeripheral signals Peripheral organsPeripheral organs

+

+

Gastrointestinaltract

Adiposetissue

FoodIntake

Adrenal glands

External factorsEmotionsFood characteristicsLifestyle behaviorsEnvironmental cues


Lifetime Food IntakeLifetime Food Intake

*kcal in millions

Water

45,300 kg

Fat

2300 kg

21 kcal*

Cholesterol

8000 kg

31 kcal*

Protein

1900 kg

7 kcal*


0 0.5 1 5

12 25 125

Cumulative Effect of Small Daily Imbalances in Energy Cumulative Effect of Small Daily Imbalances in Energy Intake on Body Fat MassIntake on Body Fat Mass

04

8

12

Excess intake (% total)

Excess intake (kcal/d)

Rosenbaum M et al. N Engl J Med. 1997;337:396-408.

1 million

Energyintake(kcal/y)

1 million

Energyexpenditure

(kcal/y)

Change in body fat (lb/y)


Consistent differences, even if very minor, between E Consistent differences, even if very minor, between E intake and E expenditure can lead to large changes in intake and E expenditure can lead to large changes in

body fat mass over time. body fat mass over time. In the USA, most adults consume approximately In the USA, most adults consume approximately

900,000 kcal per year. If energy balance were positive 900,000 kcal per year. If energy balance were positive by as little as 0.5% (12 kcal/d), 1 pound of fat would by as little as 0.5% (12 kcal/d), 1 pound of fat would be gained in 1 year. be gained in 1 year. Daily ingestion of only 5% more Daily ingestion of only 5% more

calories than expended could result in the calories than expended could result in the accumulation of approximately 6 kg (13 lb) of adipose accumulation of approximately 6 kg (13 lb) of adipose tissue in 1 year. Ingestion of only 8 kcal/d more than tissue in 1 year. Ingestion of only 8 kcal/d more than expended over 30 years could lead to an increase of expended over 30 years could lead to an increase of 10 kg in body weight, which is the average amount of 10 kg in body weight, which is the average amount of weight gained by American adults from 25 to 55 years weight gained by American adults from 25 to 55 years

of age [1]. of age [1]. Rosenbaum M et al. Obesity. Rosenbaum M et al. Obesity. N Engl J MedN Engl J Med.. 1997;337:396-408.1997;337:396-408.


The prevalence of obesity in adults in the USA The prevalence of obesity in adults in the USA increases progressively from 20 to 50 years of age, increases progressively from 20 to 50 years of age,

but begins to decline after 60 years of age. but begins to decline after 60 years of age.

The prevalence of obesity also varies by ethnicity The prevalence of obesity also varies by ethnicity and gender. Obesity is particularly common in and gender. Obesity is particularly common in

many ethnic minority women (eg, African-American, many ethnic minority women (eg, African-American, Mexican-American, Native American, Pacific Mexican-American, Native American, Pacific

IslanderIslander––American, Puerto Rican, Cuban-American). American, Puerto Rican, Cuban-American).

In last decade, incidence of Obesity had risen every In last decade, incidence of Obesity had risen every year.year.


Although genetics is an important factor in the pathogenesis of obesity, the recent increase in obesity cannot be attributed to genetics

alone and must be a result of alterations in environmental influences.

Obesity Epidemic- 50/50 ?????

However, people with certain genetic backgrounds are particularly predisposed to weight gain and obesity-related diseases,

especially when they are exposed to a precipitating lifestyle.


A striking example of this is given by the Pima Indians of Arizona. Lifestyle changes have resulted in an epidemic of obesity/diabetes within this population in the last 50 years [1].

Today, the Pimas of Arizona consume a high-fat diet (50% of E as fat) provided by government surplus commodities

rather than their traditional low-fat diet (15% of E as fat), and they are much more sedentary than when they were

farmers.


In contrast, Pima Indians who live in the Sierra Madre mountains of Northern Mexico, and consequently who have been isolated from Western influences, eat a traditional Pima diet and are physically active as farmers and sawmill workers. The Pimas of Mexico have a much lower incidence of obesity and diabetes than their genetic kindred in Arizona.

1. Pratley RE. Gene-environment interactions in the pathogenesis of type 2 diabetes mellitus: lessons learned from the Pima Indians. Proc Nutr Soc. 1998;57:175-181.

2. Ravussin E et al. Effects of a traditional lifestyle on obesity in Pima Indians. Diabetes Care 1994; 17:1067-1074.


0

10

20

30

40

50

Gene-Environment Interaction in the Gene-Environment Interaction in the Pathogenesis of ObesityPathogenesis of Obesity

Bod

y M

ass

Inde

x (k

g/m

2 )

Ravussin E et al. Diabetes Care 1994;17:1067-1074.

Pima Indians

Maycoba, Mexico Arizona

P <0.0001


Environment, not genetics, resulted in epidemic of obesity/diabetes within this population in the last 50 years.

Pima Indians an example


Medical Complications of ObesityMedical Complications of Obesity


BMI-Associated Disease RiskBMI-Associated Disease Risk

Classification BMI (kg/m2) Risk

Underweight <18.5 Increased

Normal 18.5-24.9 Normal

Overweight 25.0-29.9 Increased

Obese I 30.0-34.9 High

II 35.0-39.9 Very High

III >40 Extremely high

Clinical Guidelines on the Identification, Evaluation, and Treatment of Overweight and Obesity in Adults—The Evidence Report. Obes Res 1998;6(suppl 2).

Additional risks:• Large waist circumference (men>40 in; women >35 in)• 5 kg or more weight gain since age 18-20 y• Poor aerobic fitness• Specific races and ethnic groups


Weight (lb)

23

22

21

19

18

17

16

15

15

25

24

22

21

20

19

18

17

16

27

26

24

23

21

20

19

18

17

29

27

26

24

23

22

20

19

18

31

29

28

26

24

23

22

21

20

33

31

29

27

26

24

23

22

21

35

33

31

29

27

26

24

23

22

37

35

33

31

29

27

26

24

23

39

37

34

32

30

29

27

26

24

41

38

36

34

32

30

29

27

26

43

40

38

36

34

32

30

28

27

45

42

40

37

35

33

31

30

28

47

44

41

39

37

35

33

31

29

49

46

43

40

38

36

34

32

30

51

48

45

42

40

37

35

33

32

53

49

46

44

41

39

37

35

33

55

51

48

45

43

40

38

36

34

57

53

50

47

44

42

39

37

35

59

55

52

49

46

43

41

39

37

63

59

55

52

48

46

43

41

40

66

62

58

55

52

49

46

44

41

70

66

62

58

55

52

49

46

44

74

70

65

61

58

55

52

49

46

78

73

69

65

61

57

54

51

49

120

130

140

150

160

170

180

190

200

210

220

320

340

360

240

250

260

230

270

280

290

380

300

400

6464

Hei

ght

(in)

6262

6060

7070

6868

6666

7272

7474

7676

Body Mass Index ChartBody Mass Index Chart


0

10

20

30

40

50

60

70

Relationship Between BMI and Percent Relationship Between BMI and Percent Body Fat in Men and Women (coorelate)Body Fat in Men and Women (coorelate)

Adapted from: Gallagher et al. Am J Clin Nutr 2000;72:694.

Bo

dy

Fa

t (%

)

Body Mass Index (kg/m2)

0 10 30 40 6020 50

Women

Men


Pulmonary diseasePulmonary diseaseabnormal functionabnormal functionobstructive sleep apneaobstructive sleep apneahypoventilation syndromehypoventilation syndrome

Nonalcoholic fatty liver Nonalcoholic fatty liver diseasediseasesteatosissteatosissteatohepatitissteatohepatitiscirrhosiscirrhosis

Coronary heart diseaseCoronary heart disease

DiabetesDiabetes

DyslipidemiaDyslipidemia

HypertensionHypertension

Gynecologic abnormalitiesGynecologic abnormalitiesabnormal mensesabnormal mensesinfertilityinfertilitypolycystic ovarian syndromepolycystic ovarian syndrome

OsteoarthritisOsteoarthritis

SkinSkin

Gall bladder diseaseGall bladder disease

CancerCancerbreast, uterus, cervixbreast, uterus, cervixcolon, esophagus, pancreascolon, esophagus, pancreaskidney, prostatekidney, prostate

PhlebitisPhlebitisvenous stasisvenous stasis

GoutGout

Medical Complications of ObesityMedical Complications of Obesity

Idiopathic intracranial Idiopathic intracranial hypertensionhypertension

StrokeStroke

CataractsCataracts

Severe pancreatitisSevere pancreatitis

TYPE 2 diabetesTYPE 2 diabetes


Metabolic SyndromeMetabolic Syndrome

Abdominal obesity

Hyperinsulinemia

High fasting plasma glucose

Impaired glucose tolerance

Hypertriglyceridemia

Low HDL-cholesterol

Hypertension


Evolution of Metabolic SyndromeEvolution of Metabolic Syndrome

Isomaa B et al. Diabetes Care. 2001;24:683-689.

AKA: Insulin Resistance Syndrome; Syndrome X; Dysmetabolic Syndrome; Multiple Metabolic Syndrome

1923: Kylin describes clustering of hypertension, gout, and hyperglycemia

1988: Reaven describes “Syndrome X” – hypertension, hyperglycemia, glucose intolerance, elevated triglycerides, and low HDL cholesterol

1998: World Health Organization defines “metabolic syndrome” as clustering of hypertension, low HDL, hypertriglyceridemia, insulin resistance, glucose intolerance or type 2 diabetes, high waist-to-hip ratio, and microalbuminuria


Abdominal obesity

Glucose intolerance/ Insulin resistance

Hypertension

Atherogenic dyslipidemia

Proinflammatory/Prothrombotic state

Characteristics of the Metabolic SyndromeCharacteristics of the Metabolic SyndromeIncreases risk of DIABETES AND CVDIncreases risk of DIABETES AND CVD

National Cholesterol Educational Program (NCEP), Adult Treatment Panel (ATP) III; 2001.

DiabetesDiabetesDiabetesDiabetes CVDCVDCVDCVD


Clinical Identification of the Metabolic Clinical Identification of the Metabolic Syndrome*Syndrome*

*Diagnosis is established when >3 of these risk factors are present

Risk Factor Defining Level

Abdominal obesity

(Waist circumference)

Men >102 cm (>40 in)

Women >88 cm (>35 in)

TG >150 mg/dL

HDL-C

Men <40 mg/dL

Women <50 mg/dL

Blood pressure >130 / >85 mm Hg

Fasting glucose >110 (>100**) mg/dL

Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA. 2001;285:2486-2497.

** 2003 New ADA IFG criteria (Diabetes Care)


0

5

10

15

20

25

30

35

40

45

50

20-70+ 20-29 30-39 40-49 50-59 60-69 >70

Increasing Prevalence of Metabolic Syndrome Increasing Prevalence of Metabolic Syndrome with Age with Age

Pre

vale

nce

(%

)

Age

Men Women

Ford E et al. JAMA. 2002;287:356-359.


It is usually said that the prevalence of the It is usually said that the prevalence of the metabolic syndrome in the United States is 23 metabolic syndrome in the United States is 23

or 24%. or 24%. However, this is not a useful statement since However, this is not a useful statement since

the prevalence of the metabolic syndrome the prevalence of the metabolic syndrome markedly increases with age. markedly increases with age.

The prevalence of the metabolic syndrome is The prevalence of the metabolic syndrome is <10% in individuals aged 20<10% in individuals aged 20––29 years, 20% in 29 years, 20% in

individuals aged 40individuals aged 40––49 years, and 45% in 49 years, and 45% in individuals aged 60individuals aged 60––69 years. 69 years.

Thus it might be more useful to suggest that Thus it might be more useful to suggest that the estimated prevalence of the metabolic the estimated prevalence of the metabolic syndrome is an individual's age minus 20.syndrome is an individual's age minus 20.


0

10

20

30

40

Men Women

Prevalence of the Metabolic Syndrome Varies by Sex Prevalence of the Metabolic Syndrome Varies by Sex and Race/Ethnicity (non institutionalized >20 yrs of and Race/Ethnicity (non institutionalized >20 yrs of

age)age)P

reva

len

ce (

%)

AgeFord E et al. JAMA. 2002;287:356-359.

White

African-American

Mexican-American

Other25%

16%

28%

21%23%

26%

36%

20%


Metabolic Syndrome: Impact on Metabolic Syndrome: Impact on MortalityMortality

0

5

10

15

20

25

All-cause Mortality Cardiovascular Mortality

Mo

rta

lity

Ra

te (

%)

Without metabolic syndrome

With metabolic syndrome

*


*P < 0.001.

*


Metabolic Syndrome: Impact on Metabolic Syndrome: Impact on Cardiovascular HealthCardiovascular Health

0

5

10

15

20

25

CHD MI Stroke

Pre

vale

nce

(%

)

Without metabolic syndrome

With metabolic syndrome

*

*P < 0.001.


*

*


Ectopic Lipids and the Metabolic SyndromeEctopic Lipids and the Metabolic Syndrome

Metabolic syndrome reflects failure of intracellular lipohomeostasis, which prevents lipotoxicity in organs of overnourished individuals

Normal individuals: lipohomeostasis (ie, lipid overload confined to white adipocytes, designed to store surplus calories)

Obese individuals: adipocytes increase leptin secretion in an attempt to enhance oxidation of surplus lipid in nonadipocytes

Deficiency or nonresponsiveness to leptin prevents these protective events and results in ectopic accumulation of lipids

Pancreatic -cells and myocardiocytes are “cellular victims” – leading to type 2 diabetes and lipotoxic cardiomyopathy

Unger RH. Endocrinology. 2003.


Ectopic Lipids Ectopic Lipids or presence of fat in other or presence of fat in other

tissues in an important tissues in an important contributer to INSULIN contributer to INSULIN

RESISTANCERESISTANCECan find ectopic fatCan find ectopic fat

in liver, muscle, heart, and in liver, muscle, heart, and pancreaspancreas


0.6

1.0

1.4

1.8

2.2

2.6

3.0

Relationship Between BMI and Relationship Between BMI and Cardiovascular Disease MortalityCardiovascular Disease Mortality

Rel

ativ

e R

isk

of D

eath

Body Mass index

<18.5

MenMen

WomenWomen

Calle et al. N Engl J Med 1999;341:1097.

18.5–

20.4

20.5–

21.9

22.0–

23.4

23.5–

24.9

25.0–

26.4

26.5–

27.9

28.0–

29.9

30.0–

31.9

32.0–

34.9

35.0–

39.9

>40.0

Lean Overweight Obese


0

25

50

75

100

Relationship Between BMI and Risk of Type 2 Relationship Between BMI and Risk of Type 2 DiabetesDiabetes

Chan J et al. Diabetes Care 1994;17:961.Colditz G et al. Ann Intern Med 1995;122:481.

Age

-Adj

uste

d R

elat

ive

Ris

k

Body Mass index (kg/m2)

MenMen

WomenWomen

<22 <23 23-

23.9

24-

24.9

25-

26.9

27-

28.9

29-

30.9

31-

32.9

33-

34.9

35+

1.0

2.91.0

4.31.0

5.01.5

8.12.2

15.8

4.4

27.6

40.3

54.0

93.2

6.711.6

21.3

42.1


0

1

2

3

4

5

6

Relationship Between Weight Gain in Adulthood Relationship Between Weight Gain in Adulthood and and Risk of Type 2 Diabetes MellitusRisk of Type 2 Diabetes Mellitus

Re

lativ

e R

isk

Weight Change (kg)Willett et al. N Engl J Med 1999;341:427.

-10 -5 0 5 10 15 20

MenMen

WomenWomen


0

10

20

30

40

50

60

Direct Cost Direct Cost ** of Chronic Diseases in the of Chronic Diseases in the United StatesUnited States

Dire

ct C

ost (

$ B

illio

ns)

Type 2Diabetes

Wolf AM, Colditz GA. Obes Res. 1998;6:97-106.Hodgson TA, Cohen AJ. Med Care. 1999;37:994-1012.

*Adjusted to 1995 dollars.

Obesity CoronaryHeart

Disease

Hyper-tension

Stroke

$18.1$18.4

$38.7

$51.6$53.2


0

20

40

60

80

100

Increase in Healthcare Costs Among Obese Increase in Healthcare Costs Among Obese Compared with Lean (BMI <25 kg/m2) PatientsCompared with Lean (BMI <25 kg/m2) Patients**

Incr

ea

se in

Co

st C

om

par

ed

w

ith L

ean

Su

bje

cts

(%)

BMI 30-34 kg/m2 BMI >35 kg/m2

Quesenberry CP Jr et al. Arch Intern Med. 1998;158:466-472.

*HMO Setting: Northern California Kaiser Permanente.

Healthcare visits

Pharmacy

Laboratory tests

All outpatient services

All inpatient services

Total healthcare


Annual Medical Expenditures Attributable to Annual Medical Expenditures Attributable to Obesity in USObesity in US

Obesity prevalence for US estimated at 20% of total adult population

Prevalence varies considerably by state– Overall range: 15% (CO) – 25% (WV)

Finkelstein, et al Obes Res. 2004; 12:18-24.


Basic Principles of Obesity TherapyBasic Principles of Obesity Therapy


Obesity TherapyObesity Therapy

Adipose Adipose tissuetissue

Energy Energy IntakeIntake

Energy Energy ExpenditureExpenditure


0

0.5

1

1.5

2

2.5

3

3.5

Relationship Between Rate of Weight Relationship Between Rate of Weight Loss and Gallstone FormationLoss and Gallstone Formation

Inci

denc

e of

Gal

lsto

ne

For

mat

ion

(% s

ubje

cts/

wk)

Weinsier et al. Am J Med 1995;98:115. Reprinted with permission from Excerpta Medica.

Rate of Weight Loss (kg/wk)

0 0.5 1 1.5 2 2.5

1 2

3 45

6

7

8

9


Weight loss is associated with an increased Weight loss is associated with an increased risk of gallstones because weight loss risk of gallstones because weight loss

increases bile cholesterol supersaturation, increases bile cholesterol supersaturation, enhances cholesterol crystal nucleation, and enhances cholesterol crystal nucleation, and

decreases gallbladder contractility. decreases gallbladder contractility. The incidence of new gallstones is The incidence of new gallstones is

approximately 25%–35% in obese patients who approximately 25%–35% in obese patients who experience rapid weight loss after treatment experience rapid weight loss after treatment

with a very-low-calorie, low-fat diet (<600 with a very-low-calorie, low-fat diet (<600 kcal/d; 1–3 g fat/d) or gastric surgery. The risk kcal/d; 1–3 g fat/d) or gastric surgery. The risk

of gallstone formation increased markedly of gallstone formation increased markedly when the rate of weight loss exceeded 1.5 kg when the rate of weight loss exceeded 1.5 kg

(~1.5% of body weight) per week [5]. (~1.5% of body weight) per week [5].


Prevention of Gallstone Formation by Prevention of Gallstone Formation by Ursodeoxycholic Acid During Rapid Ursodeoxycholic Acid During Rapid

Weight LossWeight Loss


-20

-15

-10

-5

0

5

Short-term Obesity Therapy Does Not Short-term Obesity Therapy Does Not Result in Long-term Weight LossResult in Long-term Weight Loss

Cha

nge

in W

eigh

t (kg

)

Wadden et al. Int J Obes 1989;13 (Suppl 2):39.

5-yearFollow-up

1-yearFollow-up

End ofTreatment

Baseline

Diet alone

Behavior therapy

Combined therapy


-18-16-14-12-10

-8-6-4-20

Long-term Weight Loss is Improved Long-term Weight Loss is Improved with Long-term Maintenance Therapywith Long-term Maintenance Therapy

Wei

ght L

oss

(%)

Perri et al. J Consult Clin Psychol 1988;56:529.

0 1 2 3 4 5 6 7 8 9 10 11 12

Time (mo)

13 14 15 16 17

PP <0.05 <0.05

No maintenance txNo maintenance tx

Maintenance txMaintenance tx

Diet andDiet andbehaviorbehaviormodificationmodificationtherapytherapy


Obesity Treatment PyramidObesity Treatment Pyramid

DietDiet Physical ActivityPhysical Activity

Lifestyle ModificationLifestyle Modification

PharmacotherapyPharmacotherapy

SurgerySurgery


Obesity Treatment GuidelinesObesity Treatment Guidelines

The Practical GuideThe Practical Guidecan be found at:can be found at:

NHLBI web site:www.nhlbi.nih.gov

NAASO web site:www.naaso.org


Guide for Selecting Obesity TreatmentGuide for Selecting Obesity Treatment

The Practical Guide: Identification, Evaluation, and Treatment of Overweight and Obesity in Adults. October 2000, NIH Pub. No.00-4084

Treatment 25-26.9 27-29.9 30-34.9 35-39.9 >40

Diet, Exercise, Behavior Tx

+ + + + +

Pharmaco-therapy

With co-morbidities + + +

SurgeryWith co-

morbidities +

BMI Category (kg/mBMI Category (kg/m22))


Medical Benefits of Modest Weight LossMedical Benefits of Modest Weight Loss

Modest weight loss, of as little as 5% of Modest weight loss, of as little as 5% of initial body weight, can improve many of the initial body weight, can improve many of the

concurrent medical complications concurrent medical complications associated with obesity and prevent the associated with obesity and prevent the

development of new obesity-related development of new obesity-related illnesses illnesses


coronary heart disease (CHD) in men and women, coronary heart disease (CHD) in men and women, who were followed for 16 years, was directly who were followed for 16 years, was directly

related to the number of coronary heart disease related to the number of coronary heart disease risk factors (high cholesterol, low HDL-risk factors (high cholesterol, low HDL-

cholesterol, high body mass index, high systolic cholesterol, high body mass index, high systolic blood pressure, high triglyceride levels, and high blood pressure, high triglyceride levels, and high

blood glucose). blood glucose).

Each of these risk factors also is associated with Each of these risk factors also is associated with obesity. obesity.


-60

-40

-20

0

20

40

60

Relationship Between Weight Change and CHD Relationship Between Weight Change and CHD Risk Factor Sum: Framingham Offspring StudyRisk Factor Sum: Framingham Offspring Study

Wilson et al. Arch Intern Med 1999;159:1104.*P<0.002 vs baseline.

Cha

nge

in R

isk

Fac

tor

Sum

(%

)

Men Women

Weight Change During 16-y Follow-up

+20%*+37%*

*-48%*-40%

Loss >2.25 kg Gain >2.25 kg


0

50

100

150

Insulin Sensitivity Improves with Weight Loss Insulin Sensitivity Improves with Weight Loss in obese Patients with Type 2 Diabetesin obese Patients with Type 2 Diabetes

Insu

lin (

pmol

/L)

Before

Weight Loss at 1 Year (%)

Wing et al. Arch Intern Med 1987;147:1749.*P<0.01 vs before.

* *

*

0-2.4 2.5-6.9 7.0-14.0 >15


Insulin Sensitivity Insulin Sensitivity Improves with Improves with

EXERCISE even in the EXERCISE even in the absence of Weight absence of Weight

Loss in obese Loss in obese Patients with Type 2 Patients with Type 2

DiabetesDiabetes


-0.06

-0.04

-0.02

0.00

0.02

TotalCholesterol

LDL-C TG HDL-C(weightstable)

HDL-C(activelylosing)

Plasma Lipids Improve with Weight Loss Plasma Lipids Improve with Weight Loss Meta-analysis of 70 Clinical TrialsMeta-analysis of 70 Clinical Trials

m

mo

l/L k

g o

f We

igh

t Lo

ss

LDL-C=low density lipoprotein cholesterol; HDL-C=high-density lipoprotein cholesterol; TG=triglyceridesDattilo et al. Am J Clin Nutr 1992;56:320.

*P<0.05.

m

g/d

L per kg

of W

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t Lo

ss

*

**

**

0.5

0.0

-0.5

-1.0

-1.5

-2.0

-2.5


Weight loss decreases systolic Weight loss decreases systolic and diastolic blood pressure.and diastolic blood pressure.


Impact of Weight Loss on Risk FactorsImpact of Weight Loss on Risk Factors

~5%Weight Loss

5%-10%Weight Loss

HbA1c

Blood Pressure

Total Cholesterol

HDL Cholesterol

Triglycerides

1. Wing RR et al. Arch Intern Med. 1987;147:1749-1753.

2. Mertens IL, Van Gaal LF. Obes Res. 2000;8:270-278.

3. Blackburn G. Obes Res. 1995;3 (Suppl 2):211S-216S.

4. Ditschunheit HH et al. Eur J Clin Nutr. 2002;56:264-270.

1

2

3

3

1

2

3

3

4


A bit more on the Metabolic Syndrome A bit more on the Metabolic Syndrome


Metabolic Syndrome Increases Risk for Metabolic Syndrome Increases Risk for CHD and Type 2 DiabetesCHD and Type 2 Diabetes

Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA 2001;285:2486-2497.

Coronary Heart DiseaseCoronary Heart Disease

Type 2Type 2DiabetesDiabetes

HighHighLDL LDL

MetabolicMetabolicSyndromeSyndrome


Treatment of the Metabolic Syndrome in Treatment of the Metabolic Syndrome in Overweight or Obese PatientsOverweight or Obese Patients• Weight loss induced by diet and increased

physical activity is the cornerstone of therapy • Weight loss induced by drug therapy can also

improve specific features of the metabolic syndrome

• Bariatric surgery is the most effective weight loss therapy for extremely obese subjects and improves all features of the metabolic syndrome


Treatment of Metabolic Syndrome in Treatment of Metabolic Syndrome in Patients with DiabetesPatients with Diabetes• 80-85% of diabetic subjects in North America and Europe

have the metabolic syndrome• However, most subjects with the metabolic syndrome do

not have diabetes• Statin therapy is effective in diabetic subjects• Blood pressure therapy is effective in diabetic subjects


Summary: Metabolic SyndromeSummary: Metabolic Syndrome The metabolic syndrome predicts the development of both

diabetes and CHD Insulin resistance and obesity characterize most individuals

with the metabolic syndrome, although insulin resistance and obesity are not required features of the metabolic syndrome

Initial therapy for the metabolic syndrome should consist of caloric restriction and increased physical activity

Conventional cardiovascular risk factors such as lipids and blood pressure should be treated in individuals with the metabolic syndrome, although no national recommendations have so far suggested intensification of risk factor management

No consensus exists on whether insulin sensitizers should be used in nondiabetic individuals with the metabolic syndrome

slide source: leptin acts in arcuate nucleus in hypothalamus via the jak/stat pathway obese and...

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